DESCRIPTION: (provided by the applicant) Drug addiction is a chronic relapsing disease with psychological and social factors. Compulsive drug-taking is the central feature of drug addiction. Understanding the molecular mechanisms underlying the transition between controlled drug use and the loss of control over drug-taking is crucial for developing methods for the prevention and treatment of drug addiction. The neurobiological mechanisms underlying the development of uncontrolled drug-taking behaviors are associated primarily with the brain mesocorticolimbic dopamine (DA) pathway. Moreover, changes in gene expression are thought to mediate, in part, the neuroadaptive responses to the development of cocaine-taking behaviors. However, the molecular determinants and their temporal and spatial involvement in the transition from initial drug use to compulsive drug-taking behaviors remain unidentified. Based on work from our own laboratory and from others, we hypothesize that DA D1 and D3 receptors and c-Fos play important roles in the transition between controlled cocaine use and escalated cocaine intake. We propose to generate novel mouse models in which the expression of D1, D3 receptor or c-fos genes can be temporally controlled in D1 receptor-expressing neurons respectively. We propose then to test the above hypothesis by turning off the expression of D1, D3 receptor or c-fos genes in these mice during the escalation or abstinence phases and then measuring cocaine intake in an escalating cocaine self-administration paradigm. Finally, we propose to identify c-Fos-regulated target genes that are involved in the transition between controlled cocaine use to escalated cocaine intake. Successful completion of the proposed work will provide valuable information for the temporal and spatial requirement of DA D1 and D3 receptors and c-Fos in the development of compulsive drug-taking behaviors. Identification of c-Fos-regulated molecular changes involved in the transition to escalated cocaine intake will pave the way for testing the physiological significance of these changes in cocaine-taking behaviors in the future. The combined use of genetically engineered mouse models with proper behavioral and molecular biological analyses has tremendous potential to provide novel insights into mechanisms underlying the development of drug addiction and new strategies for the treatment of drug abuse.